ABSTRACT Cigarette smoking is more prevalent (50-70%) in persons living with HIV (PLWH) in the U.S. when compared with the general population and is linked to increased morbidity and mortality in this population. Furthermore, HIV-infected smokers have increased rates of cardiovascular disease, pulmonary diseases and infections, and lung cancers. Because of their high levels of nicotine dependence, low quit rates, and familiarity with harm reduction, PLWH may view use of alternative nicotine delivery products, such as electronic cigarettes (EC), an attractive option for reducing and eventually stopping combustible cigarette (CC) use. However, little is known about the health effects of EC use in PLWH. Some studies have shown that EC use was associated with increased readiness and confidence to quit smoking in the general population. However, because of their high severity of nicotine dependence, PLWH may be more likely to use both EC and CC and experience lower reduction and cessation rates. The primary objectives of this project are to examine the acceptability of EC in PLWH who are unmotivated to quit smoking, to assess the effect of EC use on smoking-related behaviors, and to assess change in cardiac and pulmonary biomarkers in PLWH who transition from CC to EC use. We propose to enroll 72 HIV-infected smokers, who decline a smoking cessation treatment referral at the time of study screening, into a randomized trial consisting of a baseline (BL) assessment visit, followed by randomization to a 6-week period of free EC distribution or usual care (control group). At weekly visits, we will assess EC and CC use, cardiac and respiratory symptoms, and perceived safety and/or harm of EC use. At BL and week 6 visits, we will measure inflammatory biomarkers and markers of tobacco toxicant exposure. At week 6, all participants will receive a smoking cessation counseling intervention and a referral to treatment. At week 12, we will assess changes in EC or CC use, quit line contact, and quit attempts. This study will be the first to examine the health effects of EC on smoking in PLWH. Given the high prevalence of smoking and the significant morbidity associated with it in PLWH, the development of effective strategies to reduce the risks related to CC smoking is critical in this group. EC may be an option for PLWH who have tried to quit and failed, and for those who are unmotivated to quit but would like to reduce the risks related to smoking while continuing to satisfy the urge to smoke. Prospective clinical studies are needed to understand whether EC have value in harm reduction by leading to a complete switch from CC to EC, reducing CC use, or by aiding in smoking cessation. Our study will provide key information on the potential benefits and harms of EC in a population that is highly dependent on nicotine and highly vulnerable to smoking-related morbidity and mortality.